The increase in transmural pressure difference, as in hypertension, leads to an increase in wall stress applied on vascular smooth muscle cells (SMCs) and cardiomyocytes. This elicits the SMC phenotype switch from contractile to synthetic and promotes the onset of remodeling processes.

Question:

In this context, we investigated the activity of myocardin, which is pivotal for development and differentiation of vascular SMCs. Myocardin is a transcriptional coactivator, which forms a ternary complex with serum response factor (SRF). As such, it binds to the CArG-box sequence of the contractile genes, such as SMA and SM22.

Results:

In vivo analyses of corresponding mouse models revealed a decrease in myocardin abundance in the media of arteries exposed to hypertension for 10 days. These data could be confirmed by ex vivo perfusion of isolated femoral mouse arteries upon a supraphysiological pressure. To investigate the mechanism in detail, cultured human arterial SMCs were exposed to cyclic stretch in vitro. This biomechanical force triggers the phosphorylation of myocardin by nuclear phosphorylated ERK1/2. HDAC 4/5 and the chaperone 14-3-3 bind to phosphorylated myocardin and mediate its translocation to the cytoplasm, where it is degraded by the proteasome.

Conclusion:

Collectively, our data indicate that an increase in wall stress attenuates the activity of myocardin by triggering its expulsion from the nucleus and its subsequent degradation. While this mechanism promotes the phenotypic switch of SMCs during the onset of vascular remodeling processes, wall stress-dependent control of myocardin activity may also be critical for the development of hypertension-dependent heart diseases.